The mechanism of polymerization of hemoglobin S is being investigated in both purified solutions and single sickle cells in order to elucidate the molecular mechanism of this progress. Theoretical analysis of kinetic data using both temperature jump and laser photolysis techniques shows that a double nucleation mechanism can quantitatively account for all of the major kinetic observations. Techniques are being developed to measure both the kinetics and thermodynamics of polymerization in the single red cells at partial saturation with oxygen or carbon monoxide. These measurements will provide the most sensitive assay for testing the potential efficacy of therapeutic agents designed to inhibit intracellular polymerization in patients with sickle cell disease.